Marcin Imieliński
@skimomiks.bsky.social
whole genome molecular oncology, genome graphs and graph genomes, cancer karyotype assembly, cancer chromosome folding, breakage fusion bridge cycles, tyfonas, and other HSRs
many 🙌 to Sukanya Panja who bravely took the 🔥 from lab alum Kofi Johnson, big 🙏 to COO-guru Paz Polak for spiritual guidance, NCI for funding, and the broader lung cancer village incl Tuomas Tammela, Carla Kim, @labjacks.bsky.social & Tere Landi for feedback over the years 22/22🧵
December 1, 2025 at 2:46 PM
many 🙌 to Sukanya Panja who bravely took the 🔥 from lab alum Kofi Johnson, big 🙏 to COO-guru Paz Polak for spiritual guidance, NCI for funding, and the broader lung cancer village incl Tuomas Tammela, Carla Kim, @labjacks.bsky.social & Tere Landi for feedback over the years 22/22🧵
While COO is not currently actionable, TOO mut patterns inform CUP diagnosis → @ecuppen.bsky.social www.nature.com/articles/s41.... LUAD vs LUSC histology also guides chemo choice. As oncology WGS becomes routine, it will be possible to link granular COO status with 💊 treatment response 21/🧵
Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary - Nature Communications
Patients with metastatic cancers of unknown primary (CUP) are currently unable to gain access to drugs through standard of care or clinical trials. Here, the authors perform whole-genome and transcrip...
www.nature.com
December 1, 2025 at 2:46 PM
While COO is not currently actionable, TOO mut patterns inform CUP diagnosis → @ecuppen.bsky.social www.nature.com/articles/s41.... LUAD vs LUSC histology also guides chemo choice. As oncology WGS becomes routine, it will be possible to link granular COO status with 💊 treatment response 21/🧵
looking forward to see how combinations of single-cell RNA-, ATAC-seq, and other multi-omic atlas-derived features can yield more granular, robust & even clinical-grade links between normal cell epigenomes and tumor somatic mutational topography 20/🧵
December 1, 2025 at 2:46 PM
looking forward to see how combinations of single-cell RNA-, ATAC-seq, and other multi-omic atlas-derived features can yield more granular, robust & even clinical-grade links between normal cell epigenomes and tumor somatic mutational topography 20/🧵
while brewing a scATAC version of this approach, we had the honor 👏 of being scooped by a beautiful recent study from (uptown colleague) Alexander Tsankov and Rosa Karlic introducing their method, aptly titled .. SCOOP → www.nature.com/articles/s41... 19/🧵
Learning the cellular origins across cancers using single-cell chromatin landscapes - Nature Communications
Understanding the cellular origins of cancers is crucial for improving diagnosis and treatment. Here, the authors utilize single cell chromatin accessibility data, patient whole-genome sequencing muta...
www.nature.com
December 1, 2025 at 2:46 PM
while brewing a scATAC version of this approach, we had the honor 👏 of being scooped by a beautiful recent study from (uptown colleague) Alexander Tsankov and Rosa Karlic introducing their method, aptly titled .. SCOOP → www.nature.com/articles/s41... 19/🧵
our methods may generalize to other cancer types and single-cell tissue atlases, in particular chromatin accessibility where classic work from Polak et al have shown strong tissue-of-origin correlations with tumor type somatic mutation density → www.nature.com/articles/nat... 18/🧵
Cell-of-origin chromatin organization shapes the mutational landscape of cancer - Nature
An analysis of cell-type-specific epigenomic features reveals a relationship between epigenomic and mutational profiles; chromatin characteristics can explain a large proportion of mutational variance...
www.nature.com
December 1, 2025 at 2:46 PM
our methods may generalize to other cancer types and single-cell tissue atlases, in particular chromatin accessibility where classic work from Polak et al have shown strong tissue-of-origin correlations with tumor type somatic mutation density → www.nature.com/articles/nat... 18/🧵
deeper analyses in larger datasets, eg massive lung cancer WGS cohorts in the landmark NCI-SHERLOCK study → www.nature.com/articles/s41... and @genomicsengland.bsky.social, may provide power to study molecular and epidemiological correlates of COO status, particularly in never-smokers 17/🧵
The mutagenic forces shaping the genomes of lung cancer in never smokers - Nature
An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as ...
www.nature.com
December 1, 2025 at 2:46 PM
deeper analyses in larger datasets, eg massive lung cancer WGS cohorts in the landmark NCI-SHERLOCK study → www.nature.com/articles/s41... and @genomicsengland.bsky.social, may provide power to study molecular and epidemiological correlates of COO status, particularly in never-smokers 17/🧵
the mapping of some LUADs to cell types associated with chronic lung injury (e.g. AT0, AT2 proliferating) may support the "cancer promoter" model put forth by @charlesswanton.bsky.social to implicate air pollutants as lung carcinogens → www.nature.com/articles/s41... 16/🧵
Lung adenocarcinoma promotion by air pollutants - Nature
Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer
www.nature.com
December 1, 2025 at 2:46 PM
the mapping of some LUADs to cell types associated with chronic lung injury (e.g. AT0, AT2 proliferating) may support the "cancer promoter" model put forth by @charlesswanton.bsky.social to implicate air pollutants as lung carcinogens → www.nature.com/articles/s41... 16/🧵
these and other hypotheses about proximal-distal lineage plasticity and driver genotypes in early LUAD evolution are readily testable in GEMM systems eg those wielded by Gardner, Varmus & Laughney in last year's tour de force → www.science.org/doi/10.1126/... 15/🧵
Lineage-specific intolerance to oncogenic drivers restricts histological transformation
Neuroendocrine-specific tolerance to Myc is an oncogenic driver underlying histological transformation of lung cancer.
www.science.org
December 1, 2025 at 2:46 PM
these and other hypotheses about proximal-distal lineage plasticity and driver genotypes in early LUAD evolution are readily testable in GEMM systems eg those wielded by Gardner, Varmus & Laughney in last year's tour de force → www.science.org/doi/10.1126/... 15/🧵
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/🧵
December 1, 2025 at 2:27 PM
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/🧵
December 1, 2025 at 2:27 PM
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/🧵
December 1, 2025 at 2:27 PM
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/🧵
December 1, 2025 at 2:27 PM
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/🧵
December 1, 2025 at 2:26 PM
..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/🧵
December 1, 2025 at 2:26 PM
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/🧵
December 1, 2025 at 2:25 PM
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/🧵
December 1, 2025 at 2:25 PM
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/🧵
December 1, 2025 at 2:24 PM
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/🧵
December 1, 2025 at 2:24 PM
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/🧵
December 1, 2025 at 2:24 PM
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/🧵
December 1, 2025 at 2:23 PM
.. 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/🧵
December 1, 2025 at 2:22 PM
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/🧵