A more complete molecular picture of lung squamous cell carcinoma comes
into view
New insights into lung tumor biology and potential drug targets emerge
from a study integrating genomics and proteomics

Date:
August 5, 2021
Source:
Broad Institute of MIT and Harvard
Summary:
Researchers have developed the largest and most comprehensive
molecular map to date of the lung cancer subtype lung squamous cell
carcinoma (LSCC). Their effort brings proteomic, transcriptomic,
and genomic data together into a detailed 'proteogenomic' view
of LSCC. Analysis of that data has revealed potential new drug
targets, immune regulation pathways that might help the cancer
evade immunotherapies, and even a new molecular subtype of LSCC.



FULL STORY ==========================================================================
Lung cancer remains the leading cause of cancer-associated death in
the United States and worldwide. Patients with a subtype called lung adenocarcinoma (LUAD) have benefited from the development of new targeted medicines, but the search for effective new therapies for another subtype called lung squamous cell carcinoma (LSCC) has largely come up short.


==========================================================================
To learn more about the biological basis of LSCC, a team led by
researchers from the Broad Institute of MIT and Harvard and the
National Cancer Institute's Clinical Proteomics Tumor Analysis
Consortium (CPTAC), including collaborators from the Baylor College
of Medicine, have developed the largest and most comprehensive
molecular map to date of LSCC. Their effort, described in Cell,
brings proteomic, transcriptomic, and genomic data together into
a detailed "proteogenomic" view of LSCC. Analysis of that data has
revealed potential new drug targets, immune regulation pathways that
might help the cancer evade immunotherapies, and even a new molecular
subtype of LSCC. Data from the study is available on the CPTAC portal (https://proteomics.cancer.gov/data-portal).

"Patients with lung squamous cell cancer have very limited therapeutic
options, and even modest success in understanding this disease could make
a difference in people's lives," said Shankha Satpathy, a group leader in
the Broad Institute's Proteomics team, and co-first and co-corresponding
author on the Cell study with co-first authors Karsten Krug and Pierre
Jean Beltran of Broad and Sara Savage of Baylor. "We hope the research community, from basic scientists to practicing oncologists, will make use
of this new resource for testing hypotheses, stimulating further research,
and opening new data-driven avenues for clinical trial design that,
in the long run, could benefit patients." Targetable opportunities In
their study, the team analyzed DNA, RNA, proteins, and post-translational protein modifications (PTMs, i.e., phosphorylation, acetylation, and ubiquitylation) of 108 tumors before treatment, and compared them with
normal tissue. Among the opportunities they saw for the development of new
LSCC treatments, the researchers identified the gene NSD3 as a possible
target for tumors harboring extra copies of FGFR1, another gene that is
often duplicated or amplified in LSCC. Prior efforts have attempted, unsuccessfully, to target FGFR1 directly. The team's proteogenomic
findings suggest that NSD3 could be a critical driver of tumor growth
and survival in these tumors, making it a potential therapeutic target.

They also noted a subset of patients whose tumors exhibited low expression
of p63 but high expression of survivin, a protein that regulates cell proliferation and cell death and which is the target of clinical trials
in other tumor types.



========================================================================== Additionally, the team's data suggested that tumors driven by
overexpression of the transcription factor SOX2 may be vulnerable
to treatments directed against chromatin modifiers such as LSD1 and
EZH2. SOX2 itself is generally considered an "undruggable" target; the
team's observations point to an opportunity to develop a therapeutic workaround.

"Proteomic and PTM data help us to see the functional effects of
the genome," explained Michael Gillette, a senior group leader in
Proteomics at Broad, an attending physician in pulmonary and critical
care medicine at Massachusetts General Hospital, and a co-senior author
on the study with Steven Carr and DR Mani of Broad and Bing Zhang of
Baylor. "Understanding which protein levels are impacted by copy-number alterations, and how mutations impact protein expression and pathway
activity, provides deeper insights into cancer biology.

"Often those insights hint at unexplored therapeutic options, or at
specific subpopulations that might benefit from specific treatments,"
he added. "This is especially important with a disease like LSCC,
where so many clinical trials have failed." Immune explorations Even
though immunotherapy represents the greatest advance in LSCC therapy
in decades, patient outcomes lag behind those seen with LUAD; only a
minority of patients with LSCC exhibit long-term responses. Based on
their proteogenomic data, the team presented a detailed picture of the
immune landscape of LSCC, highlighting several immune regulation pathways
that could serve as targetable points. In particular, their analysis highlighted a subset of tumors that exhibit markers associated with
response to immune checkpoint inhibitors (such as PD-1/PD-L1 blockers),
and with immune evasion, providing some clues as to why immunotherapy
outcomes are so uneven across patients with LSCC.



==========================================================================
"A deeper understanding of the immune landscape of LSCC tumors could
eventually lead to more effective immunotherapies and markers for
patient stratification," said Zhang, a professor in the Lester and Sue
Smith Breast Center and the Department of Molecular and Human Genetics
at Baylor.

Metabolic dysregulation and crosstalk revealed Ubiquitylation
is a process by which the cell flags proteins with another small
protein called ubiquitin (or its biochemical relatives) to target
them for destruction. While this process is important in normal
function, when dysregulated it can contribute or lead to disease. The
Broad team previously developed UbiFast, a technology that enables
deep-scale, high-throughput analysis of ubiquitylation in patient tissue samples. Applied to LSCC, UbiFast revealed complex regulation of metabolic pathways such as glycolysis and oxidative stress driven by molecular
crosstalk based on ubiquitylation (or ubiquitin-like modifications) and
two other forms of protein modification, phosphorylation (which changes
a protein's enzymatic or catalytic activity) and acetylation (which can
affect a protein's structure, activity, localization, and stability).

A new subtype emerges Prior efforts have identified four molecular
subtypes of LSCC using genomics, corresponding to distinct cell types and processes. With their proteomic perspective, the research team not only
gained a deeper understanding of immune, metabolic and proliferative
signals associated with these subtypes, but also uncovered a new epithelial-to-mesenchymal transition subtype. The cells of this new
type, they noted, may have greater potential for metastasis, but also
feature active, kinase-driven molecular pathways that could be targeted therapeutically.

"This is remarkable because LSCC tumors generally lack the types of kinase alterations present in LUAD that have been the basis for development of
a broad spectrum of therapeutic inhibitors," said Ana Robles, program
director in NCI's Office of Cancer Clinical Proteomics Research.

The study collaborators performed their work under the auspices of
CPTAC, an NCI-sponsored, multidisciplinary/multi-institutional effort
to accelerate the understanding of the molecular basis of cancer through
the application of large-scale proteogenomic analysis. This work builds
on prior studies by CPTAC and the International Cancer Proteogenomics Consortium on LUAD. All datasets generated by CPTAC are available to
the research community as a unique public resource that provides an
exceptional foundation to guide further research and support development
of therapeutic modalities in LSCC and other cancers.

"Studies like ours and others from the CPTAC network and beyond are increasingly demonstrating the importance of undertaking multi-omic, integrative analyses of tumors in order to provide a more detailed and
nuanced understanding of cancer," said Carr, senior director of Proteomics
at Broad.

"These studies have already revealed new, previously unrecognized targets
for therapeutic intervention." Support for this study was provided by the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium.

========================================================================== Story Source: Materials provided by
Broad_Institute_of_MIT_and_Harvard. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Shankha Satpathy, Karsten Krug, Pierre M. Jean Beltran, Sara
R. Savage,
Francesca Petralia, Chandan Kumar-Sinha, Yongchao Dou, Boris
Reva, M.

Harry Kane, Shayan C. Avanessian, Suhas V. Vasaikar, Azra Krek,
Jonathan T. Lei, Eric J. Jaehnig, Tatiana Omelchenko, Yifat Geffen,
Erik J.

Bergstrom, Vasileios Stathias, Karen E. Christianson, David
I. Heiman, Marcin P. Cieslik, Song Cao, Xiaoyu Song, Jiayi Ji,
Wenke Liu, Kai Li, Bo Wen, Yize Li, Zeynep H. Gu"mu"ş, Myvizhi
Esai Selvan, Rama Soundararajan, Tanvi H. Visal, Maria G. Raso,
Edwin Roger Parra, O"zgu"n Babur, Pankaj Vats, Shankara Anand,
Tobias Schraink, MacIntosh Cornwell, Fernanda Martins Rodrigues,
Houxiang Zhu, Chia-Kuei Mo, Yuping Zhang, Felipe da Veiga Leprevost,
Chen Huang, Arul M. Chinnaiyan, Matthew A.

Wyczalkowski, Gilbert S. Omenn, Chelsea J. Newton, Stephan
Schurer, Kelly V. Ruggles, David Fenyo", Scott D. Jewell, Mathangi
Thiagarajan, Mehdi Mesri, Henry Rodriguez, Sendurai A. Mani, Namrata
D. Udeshi, Gad Getz, James Suh, Qing Kay Li, Galen Hostetter,
Paul K. Paik, Saravana M.

Dhanasekaran, Ramaswamy Govindan, Li Ding, Ana I. Robles, Karl R.

Clauser, Alexey I. Nesvizhskii, Pei Wang, Steven A. Carr, Bing
Zhang, D.R. Mani, Michael A. Gillette, Clinical Proteomic Tumor
Analysis Consortium. A proteogenomic portrait of lung squamous
cell carcinoma.

Cell, 2021; 184 (16): 4348 DOI: 10.1016/j.cell.2021.07.016 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210805180655.htm

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