Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

Parth Desai; Nobuyuki Takahashi; Rajesh Kumar; Samantha Nichols; Justin Malin; Allison Hunt; Christopher Schultz; Yingying Cao; Desiree Tillo; Darryl Nousome; Lakshya Chauhan; Linda Sciuto; Kimberly Jordan; Vinodh Rajapakse; Mayank Tandon; Delphine Lissa; Yang Zhang; Suresh Kumar; Lorinc Pongor; Abhay Singh; Brett Schroder; Ajit Kumar Sharma; Tiangen Chang; Rasa Vilimas; Danielle Pinkiert; Chante Graham; Donna Butcher; Andrew Warner; Robin Sebastian; Mimi Mahon; Karen Baker; Jennifer Cheng; Ann Berger; Ross Lake; Melissa Abel; Manan Krishnamurthy; George Chrisafis; Peter Fitzgerald; Micheal Nirula; Shubhank Goyal; Devon Atkinson; Nicholas W Bateman; Tamara Abulez; Govind Nair; Andrea Apolo; Udayan Guha; Baktiar Karim; Rajaa El Meskini; Zoe Weaver Ohler; Mohit Kumar Jolly; Alejandro Schaffer; Eytan Ruppin; David Kleiner; Markku Miettinen; G Tom Brown; Stephen Hewitt; Thomas Conrads; Anish Thomas

doi:10.1016/j.xcrm.2024.101610

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

Parth Desai
, Nobuyuki Takahashi
, Rajesh Kumar
, Samantha Nichols
, Justin Malin
, Allison Hunt
, Christopher Schultz
, Yingying Cao
, Desiree Tillo
, Darryl Nousome
, Lakshya Chauhan
, Linda Sciuto
, Kimberly Jordan
, Vinodh Rajapakse
, Mayank Tandon
, Delphine Lissa
, Yang Zhang
, Suresh Kumar
, Lorinc Pongor
, Abhay Singh

Brett Schroder, Ajit Kumar Sharma, Tiangen Chang, Rasa Vilimas, Danielle Pinkiert, Chante Graham, Donna Butcher, Andrew Warner, Robin Sebastian, Mimi Mahon, Karen Baker, Jennifer Cheng, Ann Berger, Ross Lake, Melissa Abel, Manan Krishnamurthy, George Chrisafis, Peter Fitzgerald, Micheal Nirula, Shubhank Goyal, Devon Atkinson, Nicholas W Bateman, Tamara Abulez, Govind Nair, Andrea Apolo, Udayan Guha, Baktiar Karim, Rajaa El Meskini, Zoe Weaver Ohler, Mohit Kumar Jolly, Alejandro Schaffer, Eytan Ruppin, David Kleiner, Markku Miettinen, G Tom Brown, Stephen Hewitt, Thomas Conrads, Anish Thomas

Hematology Oncology

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

Original language	English
Article number	101610
Pages (from-to)	101610
Journal	Cell Reports Medicine
Volume	5
Issue number	6
DOIs	https://doi.org/10.1016/j.xcrm.2024.101610
State	Published - Jun 18 2024

Keywords

Tumor Microenvironment
Humans
Small Cell Lung Carcinoma/pathology
Lung Neoplasms/pathology
Cancer-Associated Fibroblasts/metabolism
Neuroendocrine Tumors/pathology
Neuroendocrine Cells/pathology
Female
Male
Prognosis
small-cell lung cancer
cancer-associated fibroblasts
spatial transcriptomics
intercellular communication
rapid research autopsy
tumor microenvironment
tumor heterogeneity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.xcrm.2024.101610

Cite this

Desai, P., Takahashi, N., Kumar, R., Nichols, S., Malin, J., Hunt, A., Schultz, C., Cao, Y., Tillo, D., Nousome, D., Chauhan, L., Sciuto, L., Jordan, K., Rajapakse, V., Tandon, M., Lissa, D., Zhang, Y., Kumar, S., Pongor, L., ... Thomas, A. (2024). Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities. Cell Reports Medicine, 5(6), 101610. Article 101610. https://doi.org/10.1016/j.xcrm.2024.101610

@article{3683b0d2ce6243f9931caa2352ec6767,

title = "Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities",

abstract = "Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.",

keywords = "Tumor Microenvironment, Humans, Small Cell Lung Carcinoma/pathology, Lung Neoplasms/pathology, Cancer-Associated Fibroblasts/metabolism, Neuroendocrine Tumors/pathology, Neuroendocrine Cells/pathology, Female, Male, Prognosis, small-cell lung cancer, cancer-associated fibroblasts, spatial transcriptomics, intercellular communication, rapid research autopsy, tumor microenvironment, tumor heterogeneity",

author = "Parth Desai and Nobuyuki Takahashi and Rajesh Kumar and Samantha Nichols and Justin Malin and Allison Hunt and Christopher Schultz and Yingying Cao and Desiree Tillo and Darryl Nousome and Lakshya Chauhan and Linda Sciuto and Kimberly Jordan and Vinodh Rajapakse and Mayank Tandon and Delphine Lissa and Yang Zhang and Suresh Kumar and Lorinc Pongor and Abhay Singh and Brett Schroder and Sharma, \{Ajit Kumar\} and Tiangen Chang and Rasa Vilimas and Danielle Pinkiert and Chante Graham and Donna Butcher and Andrew Warner and Robin Sebastian and Mimi Mahon and Karen Baker and Jennifer Cheng and Ann Berger and Ross Lake and Melissa Abel and Manan Krishnamurthy and George Chrisafis and Peter Fitzgerald and Micheal Nirula and Shubhank Goyal and Devon Atkinson and Bateman, \{Nicholas W\} and Tamara Abulez and Govind Nair and Andrea Apolo and Udayan Guha and Baktiar Karim and \{El Meskini\}, Rajaa and Ohler, \{Zoe Weaver\} and Jolly, \{Mohit Kumar\} and Alejandro Schaffer and Eytan Ruppin and David Kleiner and Markku Miettinen and Brown, \{G Tom\} and Stephen Hewitt and Thomas Conrads and Anish Thomas",

note = "Published by Elsevier Inc.",

year = "2024",

month = jun,

day = "18",

doi = "10.1016/j.xcrm.2024.101610",

language = "English",

volume = "5",

pages = "101610",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "6",

}

Desai, P, Takahashi, N, Kumar, R, Nichols, S, Malin, J, Hunt, A, Schultz, C, Cao, Y, Tillo, D, Nousome, D, Chauhan, L, Sciuto, L, Jordan, K, Rajapakse, V, Tandon, M, Lissa, D, Zhang, Y, Kumar, S, Pongor, L, Singh, A, Schroder, B, Sharma, AK, Chang, T, Vilimas, R, Pinkiert, D, Graham, C, Butcher, D, Warner, A, Sebastian, R, Mahon, M, Baker, K, Cheng, J, Berger, A, Lake, R, Abel, M, Krishnamurthy, M, Chrisafis, G, Fitzgerald, P, Nirula, M, Goyal, S, Atkinson, D, Bateman, NW, Abulez, T, Nair, G, Apolo, A, Guha, U, Karim, B, El Meskini, R, Ohler, ZW, Jolly, MK, Schaffer, A, Ruppin, E, Kleiner, D, Miettinen, M, Brown, GT, Hewitt, S, Conrads, T & Thomas, A 2024, 'Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities', Cell Reports Medicine, vol. 5, no. 6, 101610, pp. 101610. https://doi.org/10.1016/j.xcrm.2024.101610

TY - JOUR

T1 - Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

AU - Desai, Parth

AU - Takahashi, Nobuyuki

AU - Kumar, Rajesh

AU - Nichols, Samantha

AU - Malin, Justin

AU - Hunt, Allison

AU - Schultz, Christopher

AU - Cao, Yingying

AU - Tillo, Desiree

AU - Nousome, Darryl

AU - Chauhan, Lakshya

AU - Sciuto, Linda

AU - Jordan, Kimberly

AU - Rajapakse, Vinodh

AU - Tandon, Mayank

AU - Lissa, Delphine

AU - Zhang, Yang

AU - Kumar, Suresh

AU - Pongor, Lorinc

AU - Singh, Abhay

AU - Schroder, Brett

AU - Sharma, Ajit Kumar

AU - Chang, Tiangen

AU - Vilimas, Rasa

AU - Pinkiert, Danielle

AU - Graham, Chante

AU - Butcher, Donna

AU - Warner, Andrew

AU - Sebastian, Robin

AU - Mahon, Mimi

AU - Baker, Karen

AU - Cheng, Jennifer

AU - Berger, Ann

AU - Lake, Ross

AU - Abel, Melissa

AU - Krishnamurthy, Manan

AU - Chrisafis, George

AU - Fitzgerald, Peter

AU - Nirula, Micheal

AU - Goyal, Shubhank

AU - Atkinson, Devon

AU - Bateman, Nicholas W

AU - Abulez, Tamara

AU - Nair, Govind

AU - Apolo, Andrea

AU - Guha, Udayan

AU - Karim, Baktiar

AU - El Meskini, Rajaa

AU - Ohler, Zoe Weaver

AU - Jolly, Mohit Kumar

AU - Schaffer, Alejandro

AU - Ruppin, Eytan

AU - Kleiner, David

AU - Miettinen, Markku

AU - Brown, G Tom

AU - Hewitt, Stephen

AU - Conrads, Thomas

AU - Thomas, Anish

N1 - Published by Elsevier Inc.

PY - 2024/6/18

Y1 - 2024/6/18

N2 - Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

AB - Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

KW - Tumor Microenvironment

KW - Humans

KW - Small Cell Lung Carcinoma/pathology

KW - Lung Neoplasms/pathology

KW - Cancer-Associated Fibroblasts/metabolism

KW - Neuroendocrine Tumors/pathology

KW - Neuroendocrine Cells/pathology

KW - Female

KW - Male

KW - Prognosis

KW - small-cell lung cancer

KW - cancer-associated fibroblasts

KW - spatial transcriptomics

KW - intercellular communication

KW - rapid research autopsy

KW - tumor microenvironment

KW - tumor heterogeneity

UR - https://www.scopus.com/pages/publications/85195861807

U2 - 10.1016/j.xcrm.2024.101610

DO - 10.1016/j.xcrm.2024.101610

M3 - Article

C2 - 38897168

SN - 2666-3791

VL - 5

SP - 101610

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 6

M1 - 101610

ER -

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

Abstract

Keywords

UN SDGs

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