Haq Lab Research Overview

Our lab is dedicated to developing innovative treatments for patients with metastatic melanoma, with a specialized focus on uveal melanoma. While the last decade has seen remarkable advances in melanoma care, clinical success remains uneven. We strive to understand why therapies that are life-saving for some patients fail in others—or why they work only temporarily before resistance emerges. Our goal is to translate these molecular insights into the next generation of therapies.

1. Uveal Melanoma Biology and Treatment

Uveal melanoma (UM) is a rare but aggressive malignancy. Despite successful treatment of the primary eye tumor, approximately 50% of patients eventually develop metastatic disease, which shows a striking predilection for the liver. We have developed state-of-the-art murine models that recreate the clinical features of UM, including hematogenous spread and liver-specific colonization. Our ongoing studies address:

• Liver tropism. Why does metastasis primarily occur in the liver?
• Tumor dormancy. Why does UM often return years or decades later? We are exploring the molecular "clocks" and environmental triggers that wake dormant cells.
• Metastatic recurrence. Why does melanoma recur? We are exploring systemic influences (e.g., dietary factors) as well as microenvironmental factors (e.g., the local immune microenvironment) to uncover the determinants of recurrence. Understanding this biology will directly lead to approaches to intercept metastatic recurrence.

2. Therapeutic Resistance: From Molecular Targeting to Immunotherapy

We harness functional genomics (CRISPR/Cas9) and patient-centric biopsies to dismantle the mechanisms that allow tumors to evade treatment.

Molecularly Targeted Therapies

Our work has shown that BRAF inhibitors do more than just kill cancer cells; they paradoxically trigger "adaptive resistance" by inducing survival programs.

• Metabolic Rewiring. We demonstrated that BRAF inhibition can lead to an addiction to oxidative phosphorylation via the MITF-PGC1alpha axis (Haq et al., Cancer Cell 2013).
• Apoptotic Evasion. We continue to characterize the signaling networks that prevent cell death during treatment (Montero et al., Nature Communications 2019, Cancer Discovery 2022), aiming to develop combinatorial "triple-threat" therapies.

Immunotherapy Resistance 

By analyzing matched pre-treatment and post-resistance biopsies, we identify the genomic drivers of immune evasion:

• A role of FBXW7 and viral sensing. We discovered that loss of the tumor suppressor FBXW7 impairs dsRNA sensing (MDA5/RIG-I), allowing tumors to hide from the immune system (Gstalder et al., Cancer Discovery 2020).
• A role of SEC24 in STING trafficking and immunotherapy resistance. Our recent work identified mutations in SEC24C/D that disrupt the trafficking of STING, thereby diminishing interferon production and T-cell activation (Schiantarelli et al., Cancer Cell 2025).