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Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients., Tumors are more than cancer cells — the extracellular matrix is a protein structure that organizes all tissues and is altered in cancer. Here, the authors review recent progress in understanding how the cancer cells and tumor-associated stroma cells remodel the extracellular matrix to drive tumor growth and metastasis.

A worldwide estimate of over one million STIs are acquired daily and there is a desperate need for effective preventive as well as therapeutic measures to curtail this global health burden. Vaccines have been the most effective means for the control and potential eradication of infectious diseases; however, the development of vaccines against STIs has been a daunting task requiring extensive research for the development of safe and efficacious formulations. Nanoparticle-based vaccines represent a promising platform as they offer benefits such as targeted antigen presentation and delivery, co-localized antigen-adjuvant combinations for enhanced immunogenicity, and can be designed to be biologically inert. Here we discuss promising types of nanoparticles along with outcomes from nanoparticle-based vaccine preclinical studies against non-viral STIs including chlamydia, syphilis, gonorrhea, and recommendations for future nanoparticle-based vaccines against STIs.

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182-mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206(high) patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

The loss of miR-200 family, through DNA methylation, results in cancer cells undergoing an epithelial to mesenchymal transition (EMT), and metastasis. In this study, we established that the transcriptional repressor Kaiso directly binds methylated regions of the miR-200 family, and this is reversed with 5-aza treatment. sh-Kaiso PC-3 cells display increased miR-200-a/b/c, miR-141, and miR-429 expression, with miR-200c demonstrating the most significant increase. Interestingly, overexpression of EGFR or treatment with EGF decreases miR-200c expression and this is reversed after treatment with EGFR specific kinase inhibitor PD153035. However, EGF did not have a significant effect on miR-200c in sh-Kaiso DU-145 or PC-3 cell lines, suggesting Kaiso silences miR-200c through the activation of EGFR signaling. Overexpression of Kaiso in LNCaP cells results in decreased expression of miR-200-a/b/c, miR-141, and miR-429, along with increased expression of ZEB1, p-EGFR and total EGFR levels. Overexpression of miR200c in PC-3 cells results in decreased expression of EGFR, ZEB1, ERK1/2 and Kaiso. Additionally, sh-Kaiso PC-3 demonstrates reduced in vivo tumor formation and metastasis. Thus, our data suggests that EGFR signaling regulates the silencing of miR-200 family through Kaiso binding to methylated regions in the promoter.

Synthetic host defense peptides (HDP) are a new class of promising therapeutic agents with potential application in a variety of diseases. RP-182 is a 10mer synthetic HDP design, which selectively reduces M2-like tumor associated macrophages via engagement with the cell surface lectin receptor MRC1/CD206 and is currently being developed as an innate immune defense regulator to improve anti-tumor immunity in immunologically cold tumors. Herein, we describe a sensitive and specific liquid chromatography (LC) coupled to quadrupole electron spray tandem mass spectrometry method to measure positively charged HDPs and HDP peptide fragments in complex biological matrices. Carboxylic acid magnetic beads were used as an affinity-capturing agent to extract the positively charged RP-182 from both mouse plasma and tissue homogenates. Beads were eluted with 0.1% (v/v) formic acid and chromatographic separation was achieved on a Waters 2.1 × 100 mm, 3.5 μm XSelect Peptide CSH C18 column with a Vanguard pre-column of the same phase. MS/MS was performed on a Thermo TSQ Quantiva triple quadrupole mass spectrometer operating in Selected Reaction Monitoring (SRM) mode fragmenting the plus three parent ion 458.9(+3) and monitoring ions 624.0(+2), 550.5(+2), and 597.3(+1) for RP-182 and 462.4(+3) > 629.1(+2), 555.5(+2), and 607.3(+1) for isotopic RP-182 standard. The assay had good linearity ranging from 1 ng to 1000 ng in mouse plasma with the lower limit of detection for RP-182 at 1 ng in mouse plasma with good intra- and inter-sample precision and accuracy. Recovery ranged from 66% to 77% with minimum matrix effects. The method was successfully applied to an abbreviated pharmacokinetic study in mice after single IP injection of RP-182. The method was successfully tested on a second HDP, the 17mer D4E1, and the cationic human peptide hormone ghrelin suggesting that it might be a general sensitive method applicable to quantifying HDP peptides that are difficult to extract.

The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor’s natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression.

Additional file 5: Figure S3. E-cadherin (left) and HER2 expression in metastatic, moderately to poorly differentiated adenocarcinoma of the stomach SB.msgc-1. Immunohistochemical staining at magnification Ă 20, inlet Ă 40.

Additional file 6: Figure S4. Diagrams of different dose responses and the corresponding curve response class (CRC) scores. CRC parameters integrate potency and efficacy measurements of the compounds. Drug response curves with CRC −1.1 exhibit a near complete maximum response; −1.2 exhibit less effective maximum cell killing; −2.1 do not have a maximum response but can achieve killing of nearly all the cells; −2.2 do not have a maximum response and can only achieve intermediate killing; and 4 are inactive.

Additional file 3: Figure S1. Protein product of c.1380delA CDH1 variant predicted by MutationTaster. Wild type CDH1 sequence (UniProt ENST00000261769) shown on top, c.1380delA CDH1 variant on bottom.

Additional file 9: Figure S7. Increased induced cell death upon treatment with topoisomerase II and dual PI3K/mTOR in hereditary c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cell lines. Caspase 3/7 levels after 24 h of treatment with 1 µM mitoxantrone, 1 µM etoposide, or 1 µM PI-103 normalized to DMSO-treated control is shown (standard errors of the mean from at least 2 independent experiments done in triplicate shown).

Additional file 5: Figure S3. E-cadherin (left) and HER2 expression in metastatic, moderately to poorly differentiated adenocarcinoma of the stomach SB.msgc-1. Immunohistochemical staining at magnification Ă 20, inlet Ă 40.

Additional file 4: Figure S2. Top ten Gene Ontology (GO) cellular processes differently regulated in c.1380delA CDH1 SB.mhdgc-1 versus panel of sporadic gastric cancer cells. Enrichment analysis of all genes with FC > 2; p

Additional file 8: Figure S6. A, Target enrichment for compounds with CRC −1.1, −1.2, −2.1, or −2.2 and delta logAC50 (SB.mhdgc-1 logAC50–SB.msgc-1 logAC50) < −1. −log p values were calculated as described in materials and methods based on the total number of compounds targeting a gene or mechanism. B, LogAC50 distributions of compounds that show CRC −1.1, −1.2, −2.1, or −2.1 and logAC50

Additional file 6: Figure S4. Diagrams of different dose responses and the corresponding curve response class (CRC) scores. CRC parameters integrate potency and efficacy measurements of the compounds. Drug response curves with CRC −1.1 exhibit a near complete maximum response; −1.2 exhibit less effective maximum cell killing; −2.1 do not have a maximum response but can achieve killing of nearly all the cells; −2.2 do not have a maximum response and can only achieve intermediate killing; and 4 are inactive.

Additional file 8: Figure S6. A, Target enrichment for compounds with CRC −1.1, −1.2, −2.1, or −2.2 and delta logAC50 (SB.mhdgc-1 logAC50–SB.msgc-1 logAC50) < −1. −log p values were calculated as described in materials and methods based on the total number of compounds targeting a gene or mechanism. B, LogAC50 distributions of compounds that show CRC −1.1, −1.2, −2.1, or −2.1 and logAC50

Additional file 1: Table S1. Chromosomal aberrations detected by FISH in SB.mhdgc-1.

Additional file 4: Figure S2. Top ten Gene Ontology (GO) cellular processes differently regulated in c.1380delA CDH1 SB.mhdgc-1 versus panel of sporadic gastric cancer cells. Enrichment analysis of all genes with FC > 2; p

Additional file 7: Figure S5. Selective pharmacological vulnerabilities of c.1380delA SB.mhdgc-1 versus SB.msgc-1 gastric cancer cells identified by comparative qHTS screening with the MIPE Oncology 4.0 library. A, Bubble diagram of drug phenotypes by compound class of SB.mhdgc-1 versus SB.msgc-1 cells depicting class activities (number of compounds per drug class) measured by maximum response (max response SB.mhdgc-1 / max response SB.msgc-1). B, Bubble diagram comparing drug activities measured by potency (logAC50SB.mhdgc-1 versus logAC50SB.msgc-1).

Additional file 9: Figure S7. Increased induced cell death upon treatment with topoisomerase II and dual PI3K/mTOR in hereditary c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cell lines. Caspase 3/7 levels after 24 h of treatment with 1 µM mitoxantrone, 1 µM etoposide, or 1 µM PI-103 normalized to DMSO-treated control is shown (standard errors of the mean from at least 2 independent experiments done in triplicate shown).

Additional file 1: Table S1. Chromosomal aberrations detected by FISH in SB.mhdgc-1.

Additional file 3: Figure S1. Protein product of c.1380delA CDH1 variant predicted by MutationTaster. Wild type CDH1 sequence (UniProt ENST00000261769) shown on top, c.1380delA CDH1 variant on bottom.

Additional file 7: Figure S5. Selective pharmacological vulnerabilities of c.1380delA SB.mhdgc-1 versus SB.msgc-1 gastric cancer cells identified by comparative qHTS screening with the MIPE Oncology 4.0 library. A, Bubble diagram of drug phenotypes by compound class of SB.mhdgc-1 versus SB.msgc-1 cells depicting class activities (number of compounds per drug class) measured by maximum response (max response SB.mhdgc-1 / max response SB.msgc-1). B, Bubble diagram comparing drug activities measured by potency (logAC50SB.mhdgc-1 versus logAC50SB.msgc-1).