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Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

• Frontline communities are often excluded and tokenized in coastal resiliency planning. • Interviews with New York-area community leaders reveal pathways to better planning. • Centering and investing in community-level expertise can improve planning outcomes. • Equitable partnerships require ongoing dialogue, accountability and self-evaluation. • Iterative co-production of resiliency research yields valuable, actionable insight. Community-based organizations (CBOs) in frontline coastal communities grapple with social and environmental injustices compounded by climate change risks. In response, CBOs have developed deep expertise in climate adaptation tailored to their local communities. Yet these groups are often effectively excluded from resilience planning processes that are top-down and involve perfunctory and often performative consultations. This paper asks: What do community leaders seek from adaptation planning, and how do they recommend such processes be improved? Drawing on the experiences of ten CBOs in coastal New York and New Jersey, the majority representing BIPOC environmental justice communities, this article advances community-driven priorities for coastal resilience planning outcomes and processes. We conducted structured 60–90-minute interviews with ten CBO leaders between February-March 2022, collaboratively completed an iterative content analysis of the interview data and community plans, and workshopped core findings in multiple sessions and conversations with participating CBOs through early 2024. CBO leaders had consensus on resilience planning priorities: they oppose top-down approaches where planners bring a predetermined agenda, and seek true partnership through a relational approach that values grassroots perspectives to co-produce equitable and just strategies to address climate risk. Recommendations for decision-makers center on the need to build on existing community-led plans, invest in community leadership within planning processes, act with transparency to foster trust, partnership and co-planning with communities, and self-evaluate their practice. Lessons for researchers seeking to support community leadership within resilience planning include the need to establish lasting and mutually supportive relationships with community partners to enable knowledge co-production. [ABSTRACT FROM AUTHOR]