A Proteomic Connectivity Map for Characterizing the Tumor Adaptive Response to Small Molecule Chemical Perturbagens
Zhenzhen Zi1, Yajie Zhang1, Peng Zhang2,3
1Department of Biochemistry , UT Southwestern Medical Center , Dallas , Texas 75390 , United States.
Abstract:
A powerful means to understand the cellular function of corrupt oncogenic signaling programs requires perturbing the system and monitoring the downstream consequences. Here, using a unique pair of non-small cell lung cancer (NSCLC)/normal lung epithelial patient-derived cell lines (HCC4017/HBEC30KT), we systematically interrogated the remodeling of the NSCLC proteome upon treatment with 35 chemical perturbagens targeting a diverse array of mechanistic classes. HCC4017 and HBEC30KT cells differ significantly in their proteomic response to the same compound treatment. Using protein covariance analyses, we identified a large number of functional protein networks. For example, we found that a poorly studied protein, C5orf22, is a novel component of the WBP11/PQBP1 splicing complex. Depletion of C5orf22 leads to the aberrant splicing and expression of genes involved in cell growth and immunomodulation. In summary, we show that by systematically measuring the tumor adaptive responses at the proteomic level, an understanding could be generated that provides critical circuit-level biological insights for these pharmacologic perturbagens.
Insights
This study reveals how non-small cell lung cancer (NSCLC) cells adapt proteomically to drug treatments. Researchers identified C5orf22 as a novel splicing complex component impacting cell growth and immune response.
Area of Science:
- Proteomics
- Cancer Biology
- Molecular Oncology
Background:
- Understanding oncogenic signaling in non-small cell lung cancer (NSCLC) is crucial for targeted therapies.
- Systematic interrogation of cellular responses to chemical perturbagens aids in deciphering complex biological networks.
Purpose of the Study:
- To investigate the proteomic remodeling of NSCLC cells in response to diverse chemical treatments.
- To identify functional protein networks and novel molecular players involved in tumor adaptation.
Main Methods:
- Utilized a paired set of patient-derived non-small cell lung cancer (HCC4017) and normal lung epithelial (HBEC30KT) cell lines.
- Applied 35 chemical perturbagens across various mechanistic classes to assess proteomic changes.
- Employed protein covariance analyses to identify functional protein networks.
Main Results:
- Demonstrated significant differences in proteomic responses between NSCLC and normal lung cells upon identical compound treatment.
- Identified C5orf22 as a novel component of the WBP11/PQBP1 splicing complex.
- Showed that C5orf22 depletion results in aberrant splicing and altered expression of genes critical for cell growth and immunomodulation.
Conclusions:
- Systematic proteomic profiling of tumor adaptive responses provides critical circuit-level biological insights.
- Pharmacologic perturbagens can reveal novel molecular mechanisms underlying cancer progression and immune evasion.
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