interestingly, proximal origin LUADs with biallelic TP53 inactivation were substantially more likely to retain their non-distal identity than TP53 wild type tumors, pointing to an unexpected interplay between TP53 status and lineage plasticity 14/🧵

we next asked how plastic are distal vs. non-distal lung cell origins, analyzing both single cell and bulk transcription to identify LUADs with predominantly distal vs. non-distal cell identity 13/🧵

our analyses also linked distal origin LUADs to specific recently-discovered alveolar cell types (AT2 proliferating and AT0 cells) both associated with chronic lung injury 12/🧵

these proximal origin LUADs were strongly enriched in never-smokers and mostly wild type for KRAS 11/🧵

..but this was when lumping all LUADs and LUSCs together. what happened when we looked at tumors one-by-one? while nearly all LUSCs had proximal origins, some LUADs show non-distal origins 10/🧵

our study shows LUAD passenger mutation density is most strongly anti-correlated with AT2 gene expression, similarly LUSC with basal gene expression, consistent with their presumed cell origins 9/🧵

the most common lung cancers (LUAD and LUSC) are thought to arise from specific cell types in the distal (AT2) and proximal (basal) lung, respectively 8/🧵

could this anti-correlation help us trace lung cancers back to the COO? We leveraged recent detailed single cell atlases of normal lung from @fabiantheis.bsky.social to assess these links at various levels of the lung cell type taxonomy → www.nature.com/articles/s41... 7/🧵

but expressed in .. which cell type? since ≥ 50% somatic mutations are thought to happen before normal cells break bad (→ Tomasetti 2013 www.pnas.org/doi/full/10....) this effect should be strongest in normal cells of the lung from which lung cancers arise .. the COOs 6/🧵

how to uncover human lung cancer COOs? It has long been known (→ Pleasance 2010 www.nature.com/articles/nat...) that highly expressed genes have fewer somatic mutations, particularly for certain mutation processes (eg tobacco) 5/🧵

while GEMMs are used "prove" COO, they ultimately show , ie that cells expressing a given lineage marker (eg SPC+) give rise to tumors of a given histology (eg LUAD) in a driver context (eg Kras G12D mutant, Tp53-/-) → genesdev.cshlp.org/content/34/1... 4/🧵

.. a major confounder is lineage plasticity, both a mechanism of drug resistance in relapsed tumors (→ Rudin, @sawyerslabmskcc.bsky.social www.nature.com/articles/s41...) and a hallmark of histologically heterogenous primary LUADs (→ co-author Bill Travis www.jto.org/article/S155... 3/🧵

Classic approaches for inferring human cancer cell-of-origin (COO) rest on (shaky!) assumptions that cancer cells resemble their COO (eg by histology, transcription, methylation).. → see Visvader 2011 www.nature.com/articles/nat... 👇 2/🧵

hello @bsky.app! let's get 🍊 juices flowing with the latest from the lab → how we used whole genome passenger somatic mutation patterns 🧬 to trace the origins of never-smoker lung adenocarcinoma (LUAD) to cells of the proximal lung 🫁 @NatureGenet www.nature.com/articles/s41... 1/🧵