Dr. Santosh Kumar Sidhwan

PhD Theme/Topic: HMGA1 as a Central Regulator of EMT Programs, DNA Repair Pathways, and Immune Evasion in Colorectal Carcinoma

Supervisor: Dr. Santosh Kumar Sidhwan: Associate Professor
Contact #: 0092-3009314173
Email: santoshkumar.bumdc@bahria.edu.pk 
Campus/School/Dept: BUHSCK
RAC Approved Supervisor for Research Areas: Pathology

Supervisory Record:
PhD Produced: NA 
PhD Enrolled: NA
MPhil Produced:06
MPhil Enrolled: NA

Topic Brief Description:

Colorectal cancer (CRC) is the third most common cancer worldwide and remains a leading cause of cancer-related mortality. A major challenge in CRC management is that many patients present with or develop aggressive disease characterized by invasion, therapy resistance, and immune evasion. Conventional biomarkers (KRAS, BRAF, MSI status) provide only partial guidance and fail to predict which tumors will resist standard chemotherapy or evade immune surveillance. Recent advances highlight the role of epigenetic and transcriptional regulators in shaping CRC aggressiveness. The chromatin architectural protein HMGA1 has emerged as a critical oncogenic driver. Luo et al. (JCI, 2025) demonstrated that HMGA1 regulates chromatin accessibility at Wnt-related loci, activates the stemness regulator ASCL2, and enhances tumorigenesis in both genetic and microbial models of CRC. Importantly, they showed that HMGA1 and ASCL2 are co-upregulated in human CRC and associated with poor prognosis. However, several key gaps remain:

1. Epithelial-to-Mesenchymal Transition (EMT): While HMGA1 is known to influence EMT in some cancers, its specific role in CRC EMT and metastasis remains poorly defined.
2. DNA Repair and Therapy Resistance: Luo et al. notes activation of DNA repair genes in HMGA1-driven tumors, but whether HMGA1 functionally enhances DNA repair capacity and promotes chemoresistance has not been tested.
3. Immune Crosstalk: HMGA1 represses IL2-STAT5 signaling and T-cell response genes in mouse models, but its impact on immune infiltration and checkpoint expression in human CRC tissues is unknown.
4. Clinical Biomarker Potential: No composite biomarker exists that integrates HMGA1 expression with EMT, DNA repair, and immune phenotypes to stratify CRC prognosis or therapy response.

Together, these gaps point to an unmet opportunity; to position HMGA1 not only as a mechanistic driver of aggressiveness but also as a clinically actionable biomarker for CRC.

Research Objectives/Deliverables:

1. To define the role of HMGA1 in EMT and DNA repair-mediated therapy resistance in colorectal cancer cells.
2. To investigate the relationship between HMGA1 expression, immune infiltration, and checkpoint expression in CRC patient tumors.
3. To develop and validate an HMGA1-based biomarker panel linking EMT, DNA repair, and immune features to CRC prognosis.

Research Questions:

1. Is HMGA1 expression significantly higher in colorectal carcinoma tissues compared to adjacent normal colon tissue?
2. Is HMGA1 expression significantly higher in colorectal carcinoma tissues compared to adjacent normal colon tissue?
3. Does HMGA1 modulate the expression of DNA repair genes involved in homologous recombination and non-homologous end joining pathways (e.g., RAD51, BRCA1)?

Candidate’s Eligibility Profile:

1. The applicant must have an MPhil/Equivalent degree in Pathology with CGPA > 3.0. Besides, applicants must have a strong background in molecular pathology, and cell lines.
2. Experience with hands on for SPSS, Biorender, Mega X and Prism software is advantageous. Candidates should thrive in an international environment and have excellent communication skills to actively contribute to team research efforts.
3. Proficiency in spoken and written English is essential. We value independence and responsibility while promoting teamwork and collaboration among colleagues.